Ronald E. Merrill

About 1,200 words

Boston was the site of the VIth International Workshop on Multiple Myeloma in June. About 500 people, including a number of patients, registered for this event. What follows is an overview of the workshop from one patient's perspective. This was a scientific meeting, so this account is unavoidably somewhat technical.

The Virus Connection

The big stir at the meeting, of course, was created by the announcement of a viral connection to multiple myeloma. James Berenson and Matthew Rettig of UCLA reported that, in every myeloma patient they've tested so far, they have found Kaposi Sarcoma-associated Herpes Virus (KSHV). They did not find the virus in healthy controls, or in patients with other leukemias. In persons with MGUS, about one fourth had the virus. This certainly suggests that KSHV has a very distinct relationship to myeloma.

Surprisingly, the UCLA group found KSHV, not in the myeloma cells, but in the supporting stromal cells of the bone marrow. It has been known for a long time that the stromal cells, which might be thought of as the "soil" in which the plasma cells grow, are essential to maintaining myeloma. But it now appears that the infection with KSHV may cause the stromal cells to encourage the malignancy.

What does this mean to patients? I will defer to the official IMS statement on the KSHV study. But certainly this has to be considered a major positive development. First, because anything that so greatly advances understanding of the disease is bound to lead to more effective research. And, more directly, because it offers an entirely new approach to treatment: attacking the virus. Results won't come overnight; viral diseases are very hard to treat effectively--we can't even deal with the common cold. But eventually this could lead to, if not a cure, at least long-term control of multiple myeloma.

Advances in Treatment

The perennial debate on bone-marrow and stem-cell transplants seems to be settling into a consensus that autologous transplants offer some benefit in survival but are not curative. The best results, it seems, are achieved with early transplants (less than one year after diagnosis). Though methods for "purging" marrow or blood of myeloma cells before transplant continue to be studied, it's not clear that these techniques are yet effective. Allogeneic transplants remain very hazardous, but this may be the treatment of choice for young patients.

The other treatment controversy, alpha-interferon, was subjected to meta-analysis by a group at Oxford. Keith Wheatley reported that this statistical technique indicates a small positive effect. Use of interferon as maintenance therapy may prolong median survival by a few months.

It's now looking as though pamidronate (Aredia) not only reduces bone loss but may even improve survival somewhat.

New Drug Candidates

The notable point about new drug development for myeloma is how excruciatingly slow it is. When I reported on the 1995 Workshop, the most interesting new drugs in the pipeline were imexon and HMBA (hexamethylenebisacetamide). Both, at that time, were awaiting clinical trials. Today, almost two years later, they are still awaiting clinical trials.

Sidney Salmon's group at Arizona reported additional details about imexon. It is not myelosuppressive, which means it could be a useful adjunct to conventional therapies such as melphalan. Imexon seems to have a new mode of action; it does not bind to DNA but may work by destroying the natural antioxidant glutathione (GSH), which is needed for myeloma survival. Joseph Michaeli of Sloan-Kettering discussed HMBA, which seems to work against bcl-2, a protein that prevents the myeloma cells from undergoing natural cell death. More potent analogs of this drug are also under development.

John Lust reported that Mayo Clinic is about to begin a clinical trial of the steroid DHEA in MGUS patients to see if it might inhibit progression to multiple myeloma.

Work continues on agents such as dexverapamil, cyclosporin, and PSC-833 that might reverse resistance to existing drugs. Results have been only slightly encouraging; the immediate response is improved, but overall survival is probably not. It was suggested that it might be better to use anti-resistance agents early, to prevent resistance, rather than overcome it. Research is also discovering new drug resistance mechanisms that will have to be dealt with.

Idarubacin, a drug related to adriamycin but reportedly less toxic, has now progressed to Phase II clinical trials in the U.S. Otherwise, there's not much in the pipeline except for vinorelbine, which may show some promise as a salvage therapy.

Research and the Future

The really deep scientific stuff at the 1995 meeting was mainly about cellular responses to IL-6. This year, the focus was more on oncogenes and immune reactions.

There was increasing interest in oncogenes (and tumor suppressors) because new methods are showing that genetic abnormalities are very common in myeloma. These are not inherited; apparently they occur as the B-cell is being mutated by the body to bind to its antigen. No single type of abnormality is universal in myeloma, though some are more common than others. Understanding this problem is important, because cancer researchers are now trying to design drugs to deal with specific oncogenes.

The other hot topic was the body's own immune response to myeloma. Evidence indicates that it tries to inhibit the disease, and actually does at least "regulate" it to some extent. But eventually the immune system always loses this fight. As we understand better how this process works, perhaps it will lead to a vaccine for myeloma.

As a scientist, I enjoy watching the continuing controversy over the "malignant compartment" in myeloma--and as a patient, I believe it is one of the most critical questions for research. Myeloma plasma cells divide very slowly or not at all, and don't act much like cancer cells. Does the "real" cancer, the malignant compartment, consist of a somewhat different type of cell (B-cells, which turn into plasma cells) in the blood?

Linda Pilarski is the leading exponent of this viewpoint. If she's right, current therapies may be simply missing the target, because studies indicate that even BMT does not reduce these cells. Perhaps entirely different drugs are needed to attack them--if they are really the malignant compartment.

The Workshop included a debate between Pilarski and her long-time sparring partner Joshua Epstein, which in my opinion concluded in a mutual knock-out. The evidence increasingly mounts that the floating myeloma cells are there and are like B-cells. But, responds Epstein, why don't these cells increase with disease progression? And where is the evidence that they are more malignant than the marrow cells?

And how can all this be reconciled with the new virus results? The scientific understanding of myeloma is now more confused than ever--and that's a good sign. It marks the end of a long period of stagnant research and dead ends. When the dust settles, we'll see myeloma much more clearly.

Ronald E. Merrill, an MIT graduate, holds a PhD in chemistry. Formerly he worked in the pharmaceutical industry as a research manager; currently he does consulting and database development work. He was diagnosed with multiple myeloma in January 1993.